It has been supposed that Sphingosine-1-phosphate ((2S,3R,4E)-2-amino-3-hydroxyoctadeca-4-enyl-1-phosphate;S1P) is a lipid which is synthesized by turnover of intracellular sphingolipid and activities of extracellular secretable sphingosine kinase, acts as an intercellular or intracellular messenger. First, an experimental result which suggests S1P acts as an intracellular second messenger was reported [Science, 248, 1653(1990)]. However, it has not yet been found that S1P directly acts to intracellular molecules.
In addition, it has been suggested that S1P acts through cell-surface receptors than extracellular ones, and it has been noted that it plays a role as an intercellular messenger. Recently, cloning of S1P receptor has been made progress and it has been reported that G-protein coupled receptor, EDG-1 (S1P1), EDG-3 (S1P3), EDG-5 (AGR16/H218/S1P2), EDG-6 (S1P4) and EDG-8 (S1P5) are as specific S1P receptors.
It has been disclosed that these S1P receptors also have high homology to lysophosphatidic acid (LPA) receptor, EDG-2, 4, 7. Now, it has been considered that EDG-1-8 form S1P/LPA receptor family.
As the in vitro biological effects of S1P, cell motility inhibition of smooth muscle cells and cancer cells, platelets aggregation and the like are known. As the in vivo biological effects of S1P, vasucularization, decrease of renal blood flow, inhibition of pulmonary fibrosis and the like are known. And, it has been reported that S1P constricts canine basilar artery and renal artery [Stroke, 32, 2913(2001); British J. Pharmacol., 130, 1871(2000)].However, it has not been revealed which receptor subtypes caused such actions of S1P.
In addition, as for EDG-5, it has been reported that the mRNA expression is strongly recognized in heart, lung, stomach, and small intestine tissue. And, in arterial sclerosis model of coronary artery, mice carotid balloon injury model, it has been reported that the mRNA expression level in intima of a vessel cells significantly decrease more than in healthy ones. In EDG-5 knock-out mice, an effect on nerve system [Eur. J. Neurosci. 14, 203 (2001)], body length shortening [J. Biol. Chem. 2002] and the like have been reported.
On the other hand, WO01/03739 discloses that S1P receptor agonist or S1P inhibit various organs fibrosis. And, WO01/98301 discloses that pyrazolopyridine compounds which have an antagonistic effect to S1P receptors and those are useful in treatment for hepatic fibrosis, pulmonary fibrosis, renal fibrosis and arterial sclerosis. There is no description or suggestion about an effect on constriction of blood vessels in these both.
Besides, JP2001-261575 vaguely discloses that a therapeutic method for a improvable disease by constriction of blood vessels due to EDG-5 receptor signaling modulation or inhibition of constriction of blood vessels. However, in this specification, as EDG receptor agonist and antagonsist, there is description about only EDG-3 receptor agonist and antagonist. There is no description or suggestion about function of other Edg receptor subtypes and Edg receptor subtype selective agonist or antagonist. And, as a constriction of blood vessels, there is description about constriction of arterial blood vessels, in particular cerebral artery. There is no description or suggestion about constriction of vein.
And, 4-(4-chlorophenyl)-N-(3-(2-diisopropylamino)ethoxy)-4-methoxyphenyl)-4-hydroxy-1-piperidinecarboxamide (CAS No. 391881-92-8), N-(3-chlorophenyl)-4-(4-chlorophenyl)-4-hydroxy-1-piperidinecarboxamide(CAS No. 401642-16-8), 4-(4-chlorophenyl)-N-(3,4-dichlorophenyl)-4-hydroxy-1-piperidinecarboxamide (CAS No. 401642-17-9), methyl 2-(benzyloxy)-5-(((4-(4 -chlorophenyl)-4-(hydroxyl-1-pyperidinyl)carbonyl)amino)benzoate (CAS No. 508216-25-9), 4-(4-bromophenyl)-N-(4-chlorophenyl)-4-hydroxy-1-piperidinecarboxamide (Microsource. Co. Ltd. Cat. No. 9132838), 4-(4-bromophenyl)-4-hydroxyl-N-(3-(trifuloromethyl)phenyl)-1-piperidinecarboxamide (Microsource. Co. Ltd. Cat. No. 9132846), 4-(4-bromophenyl) -4-hydroxy-N-phenyl-1-piperidinecarboxamide (Microsource. Co. Ltd. Cat. No. 9132844) are known.